Drug preparation

ABSTRACT

Controlled release preparation containing a number of insoluble beads applied with one or more pharmaceutically active compounds, a method for the production thereof and the use in a treatment where a controlled release of a pharmaceutically active compound is needed.

This application is a continuation of application Ser. No. 07/476,988,filed on Feb. 8, 1990, abandoned which is a continuation-in-part of U.S.Ser. No. 06/907,599, filed Sep. 12, 1986 now U.S. Pat. No. 4,927,640.

FIELD OF THE INVENTION

The present invention is related to new pharmaceutical preparations withcontrolled release of a pharmaceutically active compound, to a methodfor the manufacture of such preparations and to a method of obtainingcontrolled release of a pharmaceutically active compound.

BACKGROUND OF THE INVENTION

In the medical treatment of various diseases, e.g. in thecardiovascular, gastrointestinal and chemotherapeutic field, it is anadvantage to have a constant concentration of the administered drug inthe blood. Thus a controlled release of the drug from the pharmaceuticalpreparation is wanted.

It is important that the controlled release preparation delivers theamount of drug needed to maintain an adequate and even effect during theentire therapeutic dosage interval. This usually means that the drugshould be delivered at a constant rate to give an even concentration ofthe administered drug in the blood which is of specific importance fordrugs having a small therapeutic index, i.e. a small difference betweeneffective and toxic concentration. A delayed and constant release of thedrug will also be of importance for locally irritating drugs having apotential risk of causing gastrointestinal disturbances when present inlarge local concentrations or for drugs having a short eliminationhalf-life. In the latter case less frequent administration and thusbetter patient compliance (cf. Hayes R. B. et al. Clin. Pharm. Therap.(1977), 22, pp. 125-130) may be obtained with controlled releasepreparations compared with conventional dosage forms.

A drug can be delivered in a controlled way via any route ofadministration but the preparations should preferably have some featuresin common, e.g. give a controlled and reproducible release of drug andcontribute to a reproducible absorption, have no toxic or irritatingconstituents and be suitable also for high dosage drugs.

Examples of drug delivery systems for oral use with a controlled releaseof the drug are e.g. sustained release tablets of the insoluble matrixtype, such as Durules®, and the osmotically active tablet, OROS®. TheOROS® system is described in U.S. Pat. No. 4,036,227 and in a supplementto British Journal of Clinical Pharmacology (1985), 19, 695-765 byTheeuwes F. et al. It consists of a tablet core of the drug substance asthe major constituent which is surrounded with a semipermeable polymericmembrane through which a small opening is drilled. DE-A-2030501describes a preparation of the matrix type which contains amorphoussilicon dioxide. The active compound is released by diffusion throughthe matrix. The examples above are single-unit systems with all drugsubstance concentrated in one unit while the present invention is of themultiple-unit principle.

From GB-A-1542414 a composition is known containing an organic supportmaterial to which an active compound is physically or chemically boundand a glass material in contact with said support material. The glasscontains soluble metal ions. The release of drug is governed by thedissolution of metal ions from the glass material due to an ion exchangeprocess. Obviously, the glass is not an insoluble inert compound of thecomposition.

Several advantages with depot preparations comprising a large number ofsmall units have been described in the literature. It is, for example,possible to obtain a reproducible emptying of the units from the stomachinto the small intestine when the particles are less than 1-2 mm (cf.Bogentoft C. et al: Influence of food on the absorption ofacetylsalicylic acid from enteric coated dosage forms. Europ. J. Clin.Pharmacol. (1978), 14, 351-355). Dispersion over a large area in thegastrointestinal canal can give a more reproducible total time for thepassage, which is of advantage for the absorption process (cf. Edgar B.et al: Comparison of two enteric-coated acetylsalicylic acidpreparations by monotoring steady-state levels of salicylic acid and itsmetabolites in plasma and urine. Biopharmaceutics & Drug Disposition,(1984), 5, 251-260). In addition a multiple unit preparation ispreferable to one single drug unit as the dose is spread out in theintestine. The risk of local irritation and accumulation of severaldoses due to constriction in the alimentary canal are also considered tobe lower, (cf. McMahan F. G. et al: Upper gastrointestinal lesions afterpotassium chloride supplements: A controlled clinical trial The Lancet,Nov. 13, 1059-1061).

A further advantage with a multiple unit preparation is that it may bedivided into smaller portions all having the same absorption properties.This makes it possible to obtain a greater flexibility in selecting thesize of the dose.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 represents the cumulative release, expressed in percents over aperiod of time, expressed in hours, from core of silicon dioxide, glassand sodium chloride.

FIG. 2 represents the cumulative release expressed in percents, over aperiod of time, expressed in hours, from a potassium chloride core.

FIG. 3 represents the plasma concentration of metoprolol over a periodof time.

OUTLINE OF THE INVENTION

The present invention is related to a new type of preparation giving acontrolled release of one or more pharmaceutically active compounds.

The preparation consists of a large number of small insoluble particles,cores, which are covered by a pharmaceutically active compound. Thecores have a size of 0.1-2 mm, preferably 0.1-0.5 mm, and consist ofinsoluble inert material. Insoluble means that the material is notsoluble in water, physiological fluids or in common liquids used forintravenous infusion. Examples of insoluble inert material are silicondioxide, glass, or plastic resin particles. Suitable types of plasticmaterials are pharmaceutically acceptable plastics, such aspolypropylene or polyethylene, preferably polypropylene. The corematerial should have a standardized size and shape, preferably sphericalwith an even surface. Preferably, the core material should have asufficiently high density which makes it suitable for a fluidized-bedprocess. Furthermore, it is important that the core material has a highdegree of purity, that is, is free from soluble contaminating compounds.

The pharmaceutically active compound is applied on the core materialpreferably by spraying from a solution. The active compound therebyforms a compact layer on the insoluble core. Pharmaceutically activecompounds used are such having cardiovascular, gastrointestinal orchemotherapeutic effect, especially adreneric beta-blocking agents andantibiotics. Examples of suitable pharmaceutically active compoundswhich can be applied on the core material are salts of alprenolol,metoprolol, quinidine, magnesium, and ampicillin. The resultingparticles or beads have a size of 0.2-3.0 mm, preferably 0.3-1.0 mm. Itis however possible to form controlled release preparations according tothe method above for most drugs for which such preparations are wanted,provided they can be dissolved in a solvent that can be dried off duringprocessing.

The beads according to the invention are compact, which means that theporosity is less than 15 percent.

The beads are coated with a polymeric membrane modifying and controllingthe drug release. The polymeric membrane can release the drug accordingto various release profiles, e.g. pH dependent, enteric coating, pHindependent, with or without lag time. The most important use is pHindependent controlled release in the range of pH 1-8. Examples ofsuitable polymeric materials are ethyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl phthalate (e.g.HP 55), cellulose acetate phthalate, Eudragit®RL, Eudragit®RS. Ethylcellulose can be used alone or in a combination with e.g. a watersoluble polymer such as hydroxypropylmethyl cellulose to adjust thepermeability of the coating layer.

Ethyl cellulose is available in grades having different viscosities. Inthe examples given below, ethyl cellulose qualities with a viscosity of10, 50 or 100 cps are used, but also other types of ethyl cellulose aresuitable.

Eudragit® is the trade name for a number of film coating substances onan acrylic resin basis produced by Rohm Pharma. E.g. Eudragit RL and RSare copolymers synthetized from acrylic and methacrylic acid esters witha low content of quaternary ammonium groups. The molar ratio of theseammonium groups to the remaining neutral (meth)acrylic acid esters is1:20 for Eudragit®RL and 1:40 for Eudragit®RS resulting in differentpermeability characteristics. Other variants of Eudragit that can beused are Eudragit L, Eudragit S and Eudragit E.

Pigments and/or plasticizers may be added to the polymeric solution inorder to improve the technical properties of the membrane or modify therelease characteristics. Examples of plasticizers that may be used arecitrate esters, acetylated monoglycerides, and glycerinetriacetate.

The new preparation has several advantages, e.g. the particles contain ahigh percentage of active ingredient and are not contaminated by solubleinert compounds, which is the case, when cores of e.g. lactose or sugarare covered by a therapeutically active compound. This is especiallyimportant when the preparation is used for parenteral administration.

By using small dense particles of e.g. silicon dioxide as the corematerial, it is possible to obtain highly concentrated beads (granules)of the active compound which is an advantage for high dosagepreparations, e.g. magnesium chloride.

An advantage with the new preparation is that in general less polymericmaterial is needed to obtain a delayed drug release when the insolublecores applied with an active compound are coated compared to whenpreparations having a soluble core material are coated (cf. FIG. 1). Thepreparation according to the invention can be administered by variousroutes, e.g. orally or parenterally. An example of intravenousadministration is via the drug-administration-device described inEP-B1-59694.

When using the coated beads of active compound according to thisinvention for oral application, it is possible to formulate thepreparation as granules filled into hard gelatine capsules, filled intosachets or formed into tablets and still obtain the desired plasmaconcentration profile and duration of the effect after administration.

When the small beads are tabletted they are mixed with additivescontaining e.g. microcrystalline cellulose, such as Avicel®, whichimproves the tabletting properties and facilitates the disintegration ofthe tablet to liberate the individual beads.

The invention makes it possible to obtain a decreased dosing frequencyand still have an almost constant concentration of the drug in theplasma during the whole period until the next dose is administered. Asingle dose a day is often sufficient with the new preparation.

A process for the manufacture of a controlled release preparationrepresents a further aspect of the invention. The pharmaceuticallyactive compound is dissolved in a suitable solvent e.g. methylenechloride, ethanol, isopropylic alcohol or water and sprayed onto theinsoluble core material in a coating pan or preferably in a fluidizedbed and the solvent is dried off. The beads obtained are then coatedwith a polymeric layer described above. The polymeric mixture isdissolved in a solvent such as ethanol, isopropyl alcohol and/ormethylene chloride. The spraying can be carried out in a coating pan,but is preferably carried out in a fluidized bed. Ethyl cellulose canalso be applied from an aqueous dispersion (latex).

The preparation according to the invention is particularly advantageouswhen a controlled and constant release of a therapeutically activecompound is wanted. A method for the controlled release oftherapeutically active compounds represents a further aspect of theinvention.

The invention is described in detail in the following examples:

EXAMPLES Example 1

    ______________________________________                                        Cores                                                                         ______________________________________                                        Metoprolol fumarate                                                                             1440 g                                                      Methylene chloride                                                                              9618 g                                                      Ethanol 95%       3888 g                                                      SiO.sub.2 (0.15-0.25 mm)                                                                         375 g                                                      ______________________________________                                    

    ______________________________________                                        Polymeric layer                                                               ______________________________________                                        Ethyl cellulose 10 cps                                                                              265.6     g                                             Hydroxypropylmethyl cellulose                                                                       58.4      g                                             Acetyltributylcitrate 36.0      g                                             Methylene chloride    6141      g                                             Isopropylic alcohol   1544      g                                             ______________________________________                                    

In a fluidized bed granulator metoprolol fumarate was sprayed onto thecores of silicon dioxide from a solution of ethanol 95%. 400 g of thebeads so formed (fraction 0.4-0.63 mm) were covered with the polymericsolution containing ethyl cellulose 10 cps, hydroxypropylmethylcellulose and acetyltributylcitrate by spraying a solution of thementioned substances in methylene chloride and isopropylic alcohol. Thecoated beads were then filled into hard gelatine capsules.

Examples 2-3 and Reference 1

    ______________________________________                                        Cores        2          3       Reference 1                                   ______________________________________                                        Metoprolol succinate                                                                       1440 g     1440 g  1440 g                                        Methylene chloride                                                                         9618 g     9618 g  9618 g                                        Ethanol 95%  3888 g     3888 g  3888 g                                        SiO.sub.2 (0.15-0.25 mm)                                                                    375 g                                                           Glass (0.2 mm)           375 g                                                NaCl (0.15-0.25 mm)              375 g                                        ______________________________________                                    

Polymer layer

400 g of the granules (fraction 0.4- 0.5 mm) above were coated with acomposition comprising

    ______________________________________                                        Ethyl cellulose 10 cps                                                                          52.3        g                                               Acetyltributylcitrate                                                                           8.6         g                                               Methylene chloride                                                                              1111        g                                               Isopropylic alcohol                                                                             218         g                                               ______________________________________                                    

Metoprolol succinate was sprayed onto the cores of silicon dioxide,glass and sodium chloride, respectively, from a solution of ethanol 95%and methylene chloride. The beads so formed were coated with thepolymeric solution containing ethyl cellulose 10 cps andacetyltributylcitrate dissolved in methylene chloride and isopropylicalcohol by spraying. FIG. 1 illustrates the cumulative release ofmetoprolol succinate during 20 hours. As can be seen from the figure acontrolled and almost constant release of the active compound wasobtained, when the active compound was applied on silicon dioxide orglass, whereas a core of soluble sodium chloride resulted in aconsiderably higher initial release rate, which also is illustrated inFIG. 2 (Reference 2 below) where soluble potassium chloride was used ascore material.

Reference 2

    ______________________________________                                        Cores                                                                         ______________________________________                                        Metoprolol succinate                                                                            2000 g                                                      KCl (0.1-0.2 mm)   400 g                                                      Methylene chloride                                                                              13360 g                                                     Ethanol 95%       7900 g                                                      ______________________________________                                    

400 g of the granules according to Reference 2 were coated with acomposition comprising

    ______________________________________                                        Polymeric layer                                                               ______________________________________                                        Ethyl cellulose 10 cps                                                                          135.3       g                                               Eudragit ® RS 27.4        g                                               Acetyltributylcitrate                                                                           27.4        g                                               Methylene chloride                                                                              4469        g                                               Isopropylic alcohol                                                                             661         g                                               ______________________________________                                    

The granules were formulated as described in the previous examples.

EXAMPLES 4-6

    ______________________________________                                                     Example                                                          Cores          4          5       6                                           ______________________________________                                        Metoprolol succinate                                                                         1440 g     1440 g  1440 g                                      Methylene chloride                                                                           9618 g     9618 g  9618 g                                      Ethanol 95%    3888 g     3888 g  3888 g                                      SiO.sub.2 (0.15-0.2 mm)                                                                       375 g                                                         SiO.sub.2 (0.25-0.3 mm)    375 g                                              SiO.sub.2 (0.4-0.5 mm)             375 g                                      ______________________________________                                    

400 g of the granules according to Examples 4-6 were coated with acomposition comprising

    ______________________________________                                                        granulate according to                                                        Example                                                       Polymeric layer   4        5        6                                         ______________________________________                                        Ethyl cellulose 10 cps                                                                          187.2  g     144.0                                                                              g   92.2 g                                Hydroxypropylmethyl cellulose                                                                   46.8   g     36.0 g   23.0 g                                Acetyltributylcitrate                                                                           26.0   g     20.0 g   12.8 g                                Methylene chloride                                                                              4428   g     3408 g   2168 g                                Isopropylic alcohol                                                                             1114   g     858  g   546  g                                ______________________________________                                    

The preparations were formulated as described above. In the enclosedTable 1 the release of metoprolol succinate during 20 hours is given.All preparations gave a controlled release of drug during a long periodof time.

Example 7

    ______________________________________                                        Cores                                                                         ______________________________________                                        Magnesium chloride, hexahydrate                                                                     1100 g                                                  Ethanol 99.5%         6200 g                                                  Silicon dioxide (0.15-0.30 mm)                                                                       400 g                                                  ______________________________________                                    

    ______________________________________                                        Polymeric layer                                                               ______________________________________                                        Ethyl cellulose 50 cps                                                                          533 g                                                       Methylene chloride                                                                              14107 g                                                     Isopropylic alcohol                                                                             5481 g                                                      ______________________________________                                    

Magnesium chloride (MgCl₂) was sprayed onto the cores of silicon dioxidefrom a solution of ethanol 99.5%. 400 g of the beads so formed werecoated with ethyl cellulose 50 cps from a solution of methylene chlorideand isopropylic alcohol to give granules containing 347 mg/g magnesiumchloride (MgCl₂). The in vitro release of drug was 38% after 1 hour, 58%after 2 hours and 82% after 6 hours.

EXAMPLE 8

    ______________________________________                                        Cores                                                                         ______________________________________                                        Ampicillin - Na 600 g                                                         Ethanol 95%     894 g                                                         Water purified  1020 g                                                        Glass (0.5 mm)  500 g                                                         ______________________________________                                    

    ______________________________________                                        Polymeric layer                                                               ______________________________________                                        Ethyl cellulose 100 cps                                                                           15 g                                                      Methylene chloride 600 g                                                      Isopropylic alcohol                                                                              150 g                                                      ______________________________________                                    

Ampicillin-Na was sprayed onto the cores of glass from the ethanol/watersolution. 500 g of the ampicillin-Na beads were then coated with apolymeric solution of ethyl cellulose 100 cps in methylenechloride/isopropylic alcohol. After 40 minutes in vitro dissolution 50%of the drug content was released from the beads.

EXAMPLE 9

    ______________________________________                                        Cores                                                                         ______________________________________                                        Metoprolol succinate                                                                            1440 g                                                      Methylene chloride                                                                              9618 g                                                      Ethanol 95%       3888 g                                                      SiO.sub.2 (0.15-0.25 mm)                                                                         375 g                                                      ______________________________________                                    

    ______________________________________                                        Polymeric layer                                                               ______________________________________                                        Ethyl cellulose N-10 166.2      g                                             Hydroxypropylmethyl cellulose                                                                      39.0       g                                             Acetyltributylcitrate                                                                              22.8       g                                             Methylene chloride   3889       g                                             Isopropylic alcohol  978        g                                             ______________________________________                                    

    ______________________________________                                        Tablet additives                                                              ______________________________________                                        Microcrystalline cellulose                                                                       429.3 g                                                    Corn starch        67.1 g                                                     Lactose powder     40.3 g                                                     Polyvidone         55.5 g                                                     Water purified     314.7 g                                                    Magnesium stearate  1.2 g                                                     ______________________________________                                    

    ______________________________________                                        Tablet coating (12.500 tablets)                                               ______________________________________                                        Hydroxypropylmethyl cellulose 6 cps                                                                  159.6    g                                             Polyethylene glycol 6000                                                                             39.9     g                                             Colour Titanium Dioxide                                                                              39.9     g                                             Water purified         1356     g                                             Paraffin               1.6      g                                             ______________________________________                                    

Metoprolol succinate was sprayed onto the cores of silicon dioxideaccording to the process described in the previous examples. 400 g ofthe so obtained beads (fraction 0.4-0.63 mm) were coated with thepolymeric solution described above. The coated beads of metoprololsuccinate were mixed with the additives in equal portions and afteraddition of Mg-stearate 0.1%, the dry mixture was compressed to tablets.Finally, the tablets were coated in a coating pan with the polymericsolution described above.

The very small particles, 0.15-0.25 mm, of dense SiO₂ used as the corematerial, contribute to a high content of drug in the small beads formed(0.4-0.63 mm) and thus to a reduced size of the final preparation.

EXAMPLE 10

    ______________________________________                                        Cores                                                                         ______________________________________                                        Omeprazole-Sodium     90 g                                                    Purified water       180 g                                                    Polypropylene (1.25-1.60 mm)                                                                       450 g                                                    ______________________________________                                    

    ______________________________________                                        Polymeric Layer                                                               ______________________________________                                        Ethylcellulose N 50                                                                              50 g                                                       Ethanol 99.5%     1617 g                                                      ______________________________________                                    

The manufacture was carried out in one process step using a fluidizedbed apparatus with bottom spray equipment (Wurster). Omeprazole-Sodiumwas sprayed onto the plastic cores of polypropylene from a 33% watersolution of the drug. The drug particles so formed were subsequentlycoated with the polymeric solution of ethylcellulose in ethanol. Totalyield was 88.6%.

The coated drug beads were sieved to discharge agglomerates. The beadswere analysed and were found to contain 131.1 mg Omeprazole-Sodium pergram. The in vitro release of drug in a physiological sodium chloride(0.9%) solution at 25° C. was 18% after 1 hour, 41% after 6 hours and60% after 14 hours. Method: USP dissolution apparatus No. I (rotatingbasket) at 100 rpm.

EXAMPLE 11

    ______________________________________                                        Cores                                                                         ______________________________________                                        Omeprazole-Sodium       19.5     g                                            Purified water          39       g                                            Polymethylmethacrylate (0.425-0.71 mm)                                                                100      g                                            ______________________________________                                    

    ______________________________________                                        Polymeric Layer                                                               ______________________________________                                        Ethylcellulose N 50                                                                              20 g                                                       Ethanol 99.5%     1980 g                                                      ______________________________________                                    

The same equipment and manufacturing procedures were used as in Example10. Samples were discharged from the coating process after applying 5,10 and 15 g of ethylcellulose. Total yield was 87.6%. The content ofOmeprazole-Sodium was 69.2 mg/g beads.

In vitro release results showed that the controlled release of drug ishighly dependent on the amount of film coat applied on the beads. Forexample, after 6 hours, 98%, 76% and 61% were released from the beadsbeing coated with 5, 10 and 5 g of ethylcellulose, respectively. Thesame dissolution method was used as in Example 10.

Table 1 summarizes the drug release data for the compositions accordingto examples 1-6 and 9 and Reference examples 1 and 2.

The best mode of carrying out the invention is at present considered tobe Examples 10-11.

                                      TABLE 1                                     __________________________________________________________________________    Cumulative in vitro release of metoprolol in a phosphate buffer pH 6.8        Method: USP apparatus No II, rotating paddle at 100 rpm                       Example                                                                            FIG.                                                                             Core Conc. metoprolol                                                                       Percent release over time (h)                           No.  No.                                                                              material                                                                           in the beads mg/g                                                                      1  2 3 4 6 8 10                                                                              12                                                                              14                                                                              16                                                                              18 20                              __________________________________________________________________________    1       SiO.sub.2                                                                          434      1   2                                                                               5                                                                              11                                                                              25                                                                              39                                                                              52                                                                              62                                                                              69                                                                              74                                                                              78 81                              2    1  SiO.sub.2                                                                          703      9  15                                                                              22                                                                              27                                                                              38                                                                              47                                                                              56                                                                              64                                                                              71                                                                              78                                                                              84 88                              3    1  glass                                                                              688      12 20                                                                              28                                                                              34                                                                              45                                                                              55                                                                              63                                                                              71                                                                              77                                                                              84                                                                              89 92                              Ref. 1                                                                             1  NaCl 686      5  32                                                                              51                                                                              65                                                                              81                                                                              89                                                                              93                                                                              96                                                                              98                                                                              99                                                                              100                                                                              100                             Ref. 2                                                                             2  KCl  619      8  23                                                                              32                                                                              40                                                                              53                                                                              63                                                                              73                                                                              79                                                                              84                                                                              87                                                                              90 92                              4       SiO.sub.2                                                                          513      1   2                                                                               3                                                                               8                                                                              21                                                                              34                                                                              48                                                                              61                                                                              72                                                                              80                                                                              84 88                              5       SiO.sub.2                                                                          565      1   2                                                                               4                                                                               8                                                                              19                                                                              29                                                                              40                                                                              51                                                                              62                                                                              71                                                                              78 83                              6       SiO.sub.2                                                                          620      4   8                                                                              12                                                                              17                                                                              28                                                                              37                                                                              46                                                                              54                                                                              62                                                                              68                                                                              74 79                              9    3  SiO.sub.2                                                                          533      7  13                                                                              18                                                                              23                                                                              33                                                                              43                                                                              52                                                                              61                                                                              69                                                                              76                                                                              82 86                              __________________________________________________________________________

We claim:
 1. Controlled release beads, each comprising a compact inertcore consisting of a plastic resin selected from the group consisting ofpolypropylene and polyethylene; an active layer applied to the surfaceof the insoluble core consisting essentially of one or morepharmaceutically active compounds; and a release controlling polymericmembrane covering the active layer.
 2. Beads according to claim 1wherein the core has a size of 0.1-2 mm and the combination of the coreand the layer has a size of 0.2-3.0 mm.
 3. Beads according to claim 2,wherein the core has a size of 0.1-0.5 mm and the combination of thecore and the active layer has a size of 0.3-1.0 mm.
 4. Beads accordingto claim 1 wherein the pharmaceutically active compound is to beadministered orally or parenterally.
 5. Beads according to claim 1wherein the pharmaceutically active compound is used in thecardiovascular, gastrointestinal or chemotherapeutic field.
 6. Beadsaccording to claim 1 wherein the pharmaceutically active compound isselected from the group consisting of a salt of an adrenergicbeta-blocking agent, an antibiotic and a gastric acid secretioninhibitor.
 7. A process for the preparation of beads for use incontrolled release products consisting essentially of(a) dissolving apharmaceutically active compound in a solvent; (b) applying thedissolved active compound to an insoluble core consisting of a plasticresin selected from the group consisting of polypropylene andpolyethylene having a size of 0.2 to 2.00 mm; (c) drying the insolublecore to remove the solvent and form beads having a coating of activecompound and a size of 0.2 to 3.0 mm; and (d) further coating the beadswith a release controlling polymeric membrane.